Stem cells have been trumpeted as the solution for alleviating the serious shortage of tissue and organs for transplantation. To date, numerous types of naturally occurring and artificially produced stem cells have been identified or created. However, every one of them has their own shortcomings. Induced pluripotent stem cells (iPSCs), produced from reprogramming of somatic cells such as skin fibroblasts (Takahashi and Yamanaka, Cell, 126(4):663-76 (2006)), is currently regarded as the best candidate for use in regenerative medicine. However, iPSC generation remains a very slow (˜4 weeks) and inefficient (<0.01%) process that results in a heterogeneous population of cells, and requires specific expertise in human pluripotent cell culture (Takahashi et al., Cell, 131, 861-72 (2007); Yu et al., Science, 318, 1917-20 (2007)). An alternative approach is to use a small chemical molecule that can directly activate the pluripotent genes Oct4, Sox2 and Nanog.
Programin was first synthesized by Chen et al. (J. Am. Chem. Soc., 2004 126: 410-411). It was used to transdifferentiate C2C12 myogenic cells into osteocytes and adipocytes. Subsequently, it was shown that the polycomb genes in C2C12 were probably involved in the transdifferentiation process using comparative proteomic techniques (Shen et al., Proteomics, 2007, 7(23): 4303-4316). Furthermore, it was reported that treating fibroblasts with reversine could induce them to transdifferentiate into skeletal muscle cells (Luigi et al., 2007, Cell Death and Differentiation, 13(12): 2042-2051; Chiara et al., 2009, Electrophoresis, 30(12): 2193-2206). Mandal et al. (Biochip Journal, 2013, 7(3): 278-287) examined the transcriptome profile of reversine-mediated transdifferentiation of NIH3T3 fibroblasts into osteoblasts. The study did not show that reversine activated the expression of pluripotency genes such as Oct4, Sox2 and Nanog.
There is a need for simple and efficient methods based on the use of small molecule compounds to generate iPSCs. The present invention meets this and other needs.